Defining cell intrinsic and extrinsic regulators of ferroptosis in pancreatic cancer

项目摘要 胰腺癌，最常被诊断为胰腺导管腺癌（PDAC）， 是美国癌症死亡的三大主要原因之一。这些肿瘤是众所周知的 抗细胞凋亡，并富含基质和免疫细胞， 微环境免疫治疗对患者的生存没有好处，尽管联合治疗取得了进展， 化疗的5年生存率约为11%。因此，研究细胞死亡的替代形式 是针对PDAC的独特策略。铁凋亡是一种最近描述的细胞死亡形式， 从细胞凋亡。它依赖于脂质过氧化物的积累，由游离不稳定铁产生，导致 渗透性细胞裂解。靶向铁凋亡可以有效地诱导培养的PDAC细胞中的细胞死亡。然而，在PDAC中， 在小鼠肿瘤中，触发铁凋亡具有适度的反应，具有固有和获得性的不同情况。 耐药性目前限制了其治疗效用。因此，我们迫切需要解决国际社会与国际社会之间的差距， 用于未来临床研究的体外和体内反应。为了实现这一点，我采取了一种简化的方法， 提取通过渗透和还原-氧化（氧化还原）力调节铁凋亡的机制。 从机制上讲，已知铁凋亡需要渗透压来诱导细胞溶解，但这一事实并非如此。 在目前越来越多的关于癌症中的铁凋亡的文献中得到了很好的研究。我们假设细胞死亡是通过 铁凋亡需要氧化还原代谢的失衡和足够的渗透压，PDAC细胞对这两种代谢的平衡起作用。 尤其脆弱。目的研究渗透压和氧化还原之间的生化依赖性 新陈代谢. AIM II将外部渗透压的变化与细胞生物化学的变化区分开来， 适应，从单层扩大到3D培养技术。总之，这些目标调查是否 铁凋亡细胞死亡可以简化为氧化还原和渗透压的平衡。本项目的总体目标 研究的目的是概述这些参数的边界，并探索它们在靶向铁凋亡中的应用。 PDAC的。

Project Summary Pancreatic cancer, most commonly diagnosed as pancreatic ductal adenocarcinoma (PDAC), is amongst the top three leading causes of cancer death in the United States. These tumors are notoriously resistant to apoptosis and richly populated by stromal and immune cells that create a therapy-resistant microenvironment. Immunotherapy shows no benefit to patient survival, and despite advances in combinational chemotherapy the 5-year survival rate sits around 11%. Therefore, investigating alternative forms of cell death represents a unique strategy for targeting PDAC. Ferroptosis is a recently described form of cell death distinct from apoptosis. It is dependent on an accumulation of lipid peroxides, generated by free labile iron, resulting in osmotic cell lysis. Targeting ferroptosis can potently induce cell death in cultured PDAC cells. Yet, in PDAC tumors in mice, triggering ferroptosis has a modest response with distinct cases of intrinsic and acquired resistance currently limiting its therapeutic utility. It is therefore urgent that we address the gap between the in vitro and in vivo responses for future clinical studies. In pursuit of this, I am taking a reductionist approach to distill the mechanisms that regulate ferroptosis by osmotic and reductive-oxidative (redox) forces. Mechanistically, it is known that ferroptosis requires osmotic pressure to induce cell lysis, but this fact is not well studied within the current growing literature on ferroptosis in cancer. We hypothesize that cell death via ferroptosis requires an imbalance of redox metabolism and sufficient osmotic pressure, to which PDAC cells are particularly vulnerable. AIM I studies the biochemical dependencies between osmolarity and redox metabolism. AIM II distinguishes changes in the external osmotic pressure from the cellular biochemical adaptations, scaling up from monolayer to 3D culture techniques. Together, these aims investigate whether ferroptotic cell death can be simplified to a balance of redox and osmotic pressure. The overall goals of this study are to outline the boundary of these parameters and explore their application for targeting ferroptosis in PDAC.